Quinolones are a family of antibiotics with broad spectrum antibacterial properties used to treat a wide range of infections, including both Gram-positive and Gram-negative bacterial infections. The basic pharmacophore, or active structure, of the quinolone class is based upon the quinoline ring system (Schaumann, R.; Rodloff, A. C. (January 2007). “Activities of Quinolones Against Obligately Anaerobic Bacteria” Anti-infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry—Anti-Infective Agents) (Bentham Science Publishers) 6 (1): 49-56). The majority of quinolones in clinical use are fluoroquinolones, which have a fluorine atom attached to the central ring system, typically at the 6-position.
Non-steroidal anti-inflammatory drugs (NSAIDs) are an important therapeutic class of drugs also commonly used in the control of inflammation and provide analgesia in a range of diseases and following surgical intervention. For example NSAIDs are increasingly being used in ophthalmology practice in treating a range of conditions and as a preventative measure following surgery. NSAID drops have been found to ameliorate pain and reduce the signs of ocular inflammation, including postoperative cells and flare within the anterior chamber following ocular surgery (Kabat and Sowka Review of Optometry (2013) June 16 and references sited therein). They have also been found to reduce the incidence of cystoid macular oedema (CME).
Many of the existing drug delivery systems are only effective at delivering drugs that have molecular masses that are only up to a few hundred Daltons, exhibit octanol-water partition coefficients that heavily favor lipids and require doses of milligrams per day or less (Prausnitz M R, Mitragotri S, Langer R. Current status and future potential of transdermal drug delivery. Nat Rev Drug Discov. 2004; 3:115-124). Such systems are ineffective at delivering low potency and hydrophilic drugs. Almost all antiobitics require doses of tens of milligrams per day or more and are relatively hydrophilic drugs. It is desirable to be able to deliver such antibiotics directly to the site of infection in a controlled manner over an extended period of time.
To treat eye infection fluoroquinolone antibiotics are presently formulated as eye drops, which if administered conscientiously to the affected eye will prevent infection or treat an established infection. The fluoroquinolone antibiotics are administered as eye drops, either alone (i.e. as a single agent) or in combination. For example, some pharmaceutical preparations used in post-surgical eye care, such as Ciloxan™, Zymar™, Zymaxid™, Quixan™, LQuix™ and Vigamox™ eye drops marketed by Alcon, Allergan, Allergan, Vistakon Pharmaceuticals LLC, Santen, and Alcon, respectively, Acular™, marketed by Allergan and Prolensa™ and Bromday™ eye drops marketed by ISTA Pharmaceuticals.
It is postulated that combining quinolones with non-steroidal anti-inflammatory drugs (NSAIDs), may provide an additive effect in post-surgical care by both preventing infection, providing analgesia and treating inflammation.
Unfortunately, as ocular surgery is more prevalent in the elderly many patients do not have the drop competence to administer their drops effectively, compromising therapy. A recent study by An et al showed that drop competence in the elderly is poor with only 7.4% of patients capable of administering their drops effectively following cataract surgery (An J A, Kasner O, Samek D A, Levesque V. Evaluation of eye drop administration by inexperienced patient after cataract surgery. J Cataract Refract Surg., 2014; 40:1857-1861). Drop competence in post-surgical drop therapy is therefore an issue.
Drug delivery systems have been developed to aid in the administration and/or sustained delivery of bioactive agents (such as drugs) to a desired site of action. One mode of delivering a drug to a subject involves the use of a polymer in association with the drug so that it can be delivered to and/or retained at a specific location.
One form of a polymer/drug delivery system utilises an admixture of a polymer with a drug, where the drug is blended with the polymer matrix. However, such admixtures generally result in poor control over the release of the drug, with a “burst effect” often occurring immediately after administration and significant changes in the physical properties of the admixture occurring as the drug is released (Sjoquist, B.; Basu, S.; Byding, P.; Bergh, K.; Stjernschantz, J. Drug Metab. Dispos. 1998, 26, 745.). In addition, such admixtures have limited dose loading capacity, resulting in a prohibitively large device for convenient administration to some sites in a subject. As more drugs are added the system becomes more complex and the ability to control the release of each drug more difficult.
Polymer-bioactive agent conjugates, offer one approach that has been used in an attempt to provide targeted drug delivery of NSAIDs and fluoroquinolones. Polymer-bioactive agent conjugates can be prepared by covalently reacting a bioactive agent-functionalised monomer having at least two terminal reactive functional groups, with a co-monomer of complementary terminal functionality. An example is the reaction of a drug-functionalised dihydroxy monomer with a diisocyanate co-monomer to form a polymer-drug conjugate with a polyurethane polymer backbone. However, one problem with polymerisation methods is that the NSAIDs and quinolones which contain multiple nucleophilic functional groups may react with a terminal functional group of a monomer, leading to intra-chain incorporation of the bioactive agent in the polymer. As a result, the bioactive agent becomes part of the polymer backbone structure, rather than forming a pendant group.
Systems which take advantage of the option of in chain incorporations are described in U.S. Pat. No. 6,613,807, WO2008/128193, WO94/04593 and U.S. Pat. No. 7,122,615. However, such polymer systems generally provide inefficient delivery of the drug, as release of the drug relies on breakdown of the polymer backbone. Furthermore, breakdown of the polymer backbone produces inactive intermediates. Such intermediates can complicate regulatory approval, which may require the safety of the intermediates to be demonstrated. Also this strategy does not readily allow for multiple drugs to be incorporated due to differences in reactivity and biodegradation.
For efficient delivery, bioactive agents such as drugs are ideally pendant from the backbone polymer chain. One approach for preparing pendant active agent conjugates involves the covalent attachment of bioactive agent molecules to a pre-formed polymer backbone. Examples of such polymer conjugates have been reviewed in Nature Reviews: Drug Discovery 2003:2, 347-360. However, this approach can also be problematic. In particular, steric and thermodynamic constraints can affect the amount of bioactive agent that can be covalently attached, and also impact on the distribution of the bioactive agent along the polymer backbone. These factors can, in turn, reduce control over the release of the bioactive agent. Furthermore, the use of a pre-formed polymer backbone provides limited scope for modification of the polymer conjugate after attachment of the bioactive agent should the properties of the conjugate need to be adjusted to improve drug release and/or to aid patient comfort, particularly in the eye.
In US2015/0150999, we have shown that NSAIDs of the aryl carboxylic acid class may be conjugated pendant to a polyurethane-ester backbone through the carboxylic acid of the NSAID. To ensure therapeutic levels of drug release the NSAID need to be conjugated to the polymer backbone via an aryl ester. It was also found that the desired level of release often called for the use of relatively high stoichiometric amounts of a hydrophilic component (e.g. PEG), which in turn limits the maximum dose load that can be achieved. Moroever, there was a risk of in-chain incorporation for any NSAID that had another nucleophilic functional group (e.g. diclofenac or bromfenac) during the step-growth polymerisation process used to make the conjugate.
Flouroquinolone-polymer conjugates have been described by Parwe et al (Parwe et al Int J Nanomed (2014) Vol 9 pp 1463-1477), Roseeuw et al (Roseeuw et al Antimcrobial Agents and Chemotherapy (2003) Vol 47(11) pp 3435-1441), Gac-Bretin et al (Gac-Bretin et al J Drug Targeting (2004) Vol 12(5) pp 297-307) and Schmidt et al (Schmidt et al Bioconjugate Chem (2015) Vol 26(9) pp 1950-1962) and in all cases the fluoroquinolone is conjugated through an amine functionality opposite to the common carboxylic acid functional group of the fluoroquinolone. The precise linkage used varies with each fluoroquinolone according to the precise amine functional group of each fluoroquinolone. It would be advantageous to use the common carboxylic acid associated with the fluoroquinolone moiety so the delivery system may the broadly applicable to all fluoroquinolones of the class and ensure the rate of delivery of the fluoroquinolone is consistent across all drugs in the class.
It is also desirable to provide a polymer structure which allows manufacturers to achieve high loadings of the drugs pendant to the backbone. Polymerisation of a number of co-monomers, in addition to an active monomer, is frequently required in many systems in order to provide optimal biodegradation of the backbone and the required rate of drug release. This can result in blocks of inactive monomer and generally reduces the dose load of the active monomer units. It would be advantageous to increase the drug load by reducing the number of monomer components required to make the drug-polymer conjugate.
It is also desirable to use a polymer structure which allows manufacturers to achieve consistent stoichiometry of each monomer component used to make the final conjugate. A propensity for uneven distribution of monomer components through the final backbone exists if more than one monomer is used to make the final conjugate. For example, use of an active drug-monomer diol and PEG diol with a common diisocynate comonomer can result in block-polymer character due to differences in the reactivity of the active drug-monomer diol and PEG diol. A propensity of uneven distribution may contribute to batch-to-batch variation in manufacture of the conjugate.
It would be desirable to provide new polymer-bioactive agent conjugates, which address or ameliorate one or more disadvantages or shortcomings associated with existing materials and/or their method of manufacture, or to at least provide a useful alternative to such materials and their method of manufacture.